EP0134946A1 - 3,6-Disubstituierte Triazolo[3,4-a]phthalazinderivate - Google Patents

3,6-Disubstituierte Triazolo[3,4-a]phthalazinderivate Download PDF

Info

Publication number
EP0134946A1
EP0134946A1 EP84107562A EP84107562A EP0134946A1 EP 0134946 A1 EP0134946 A1 EP 0134946A1 EP 84107562 A EP84107562 A EP 84107562A EP 84107562 A EP84107562 A EP 84107562A EP 0134946 A1 EP0134946 A1 EP 0134946A1
Authority
EP
European Patent Office
Prior art keywords
formula
phenyl
alkyl
triazolo
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP84107562A
Other languages
English (en)
French (fr)
Other versions
EP0134946B1 (de
Inventor
Emilio Occelli
Giorgio Tarzia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruppo Lepetit SpA
Original Assignee
Gruppo Lepetit SpA
Lepetit SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruppo Lepetit SpA, Lepetit SpA filed Critical Gruppo Lepetit SpA
Priority to AT84107562T priority Critical patent/ATE28874T1/de
Publication of EP0134946A1 publication Critical patent/EP0134946A1/de
Application granted granted Critical
Publication of EP0134946B1 publication Critical patent/EP0134946B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals

Definitions

  • the present invention is directed t Q new 3,6-disubstituted-1,2,4-triazolo[3,4-a] phthalazine derivatives, to the process for their preparation and to the pharmaceutical compositions containing them.
  • the present invention also encompasses the pharmaceutically-acceptable acid-addition salts of these compounds.
  • substituted phenyl is intended to refer to a phenyl group wherein one, two or three hydrogens are replaced by groups each independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halogen, phenyl, hydroxy, amino, mono- and di-(C I -C 4 )alkylamino, (C 2 -C 4 )alkanoylamino and trifluoromethyl.
  • alkyl or “alkoxy” per se, as well as the alkyl or alkoxy portions in other substituents containing said moieties, designate straight or branched alkyl or alkoxy groups which contain a number of carbon atoms within the range specified between parenthesis.
  • (C 1 -C 4 )alkyl designates a straight or branched alkyl radical which may contain 1, 2, 3 or 4 carbon atoms.
  • halogen identified chlorine, bromine, fluorine and iodine atoms.
  • saturated 4, 5, 6 or 7 membered heterocyclic rings are: oxazolidinyl isoxazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, pyrazinidyl, pyrimidinyl pyridazinidyl, morpholinyl, imidazolidinyl, piperazinyl, triazolidinyl, perhydroazepinyl, perhydro- diazepinyl and the like.
  • “Pharmaceutically-acceptable acid-addition salts” are the acid addition salts of the compounds of formula I which are not toxic, i.e. whose anion is relatively harmless at dosages compatible with good antianxiety activity in animals so that the pharmacological effects of the compounds of the invention are not impaired by possible side-effects of the anion.
  • compositions of formula I are the acid-addition salts of the selected compounds of formula I with mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, or with organic, carboxylic or sulfonic acids, such as lactic, succinic, oxalic, citric- tartaric,
  • a preferred group of compounds of the invention includes those compounds of formula I wherein R is phenyl or substituted phenyl, and R 1 is an amine of formula NR 4 R 5 , wherein R 4 and R 5 are as defined above.
  • a further group of preferred compounds includes those compounds of formula I wherein R is phenyl and R 1 is NR 4 R 5 wherein R 4 and R 5 represent (C I -C 4 )alkyl groups or (C 1 -C 4 )alkyl groups substituted as defined above or R 4 and R 5 taken together with the adjacent nitrogen atom represent a pyrrolidino, pyrazolidino, piperidino, imidazolidino and morpholino group.
  • the compounds of the present invention when tested in vitro in the benzodiazepine receptor binding test, showed to act selectively on the rat brain benzodiazepine receptors displacing 3 H-diazepam from its specific receptors with a considerable potency. Furthermore, the compounds of the present invention showed to be able to displace 3 H-diazepam from its specific brain receptors also when tested in vivo.
  • This activity on benzodiazepine receptors is known to reflect, and actually reflects, an antianxiety activity which is detectable in animals by the pharmacological tests usually employed in this field. Said activity is of particular interest in that at the effective doses tested, it is not accompanied by the side effects typically associated to benzodiazepines, such as sedation, motor incoordination, etc.
  • a general method for preparing the compounds of the invention is a multistep procedure which comprises the alcoholysis of a cyano-triazolo-phthalazine of the following formula II wherein R, R 2 and R 3 are as defined above, to give the corresponding lower alkyl ester of formula III which is in turn reduced to the corresponding alcohol derivative of formula IV
  • the alcoholic function of the triazolo-phthalazine derivative of formula IV is then substituted with a "good leaving group” function, such as a halogen atom or an ester-reactive function to give a triazolo-phthalazine derivative of formula V wherein X is a "good leaving group” as above defined.
  • a "good leaving group” function such as a halogen atom or an ester-reactive function
  • esters-reactive functions which can be used in this reaction step are sulfonic esters such as the mesilate, tosylate and the like.
  • esters-reactive functions are especially preferred when the substrate of the reaction is a 1,2,4-triazolo-phthalazine of the above formula wherein n is equal to 2.
  • the alcoholysis of the cyano-triazolo-phthalazine of formula II is conducted by treating a mixture of the compound of formula II in a lower alkanol with hydrogen chloride and hydrolyzing the iminoester hydrochloride so obtained to give the corresponding carboxylic ester, which is recovered by filtration and purified, if necessary or desired, by crystallization.
  • the subsequent reduction of the ester derivative of formula III employs an alkali metal boron hydride, such as NaBH 4 or LiBH 4' which are usually used in reducing an ester function to an alcohol one.
  • an alkali metal boron hydride such as NaBH 4 or LiBH 4' which are usually used in reducing an ester function to an alcohol one.
  • other reducing agents such as LiAlH 4 , A1H 3 , LiAlH(OCH3)3 or NaBH(OCH 3 ) 3 can be used.
  • This reaction is carried out in the presence of a suitable polar aprotic inert organic solvent.
  • a suitable polar aprotic inert organic solvent Preferably the reaction is conducted at the reflux temperature for some hours, and the reaction course is monitored by means of TLC.
  • the hydroxy intermediate of formula IV is then recovered by means of known per se techniques which includes removing the reducing-agent excess, evaporating the solvent under reduced pressure, washing the crude residue with water and drying it.
  • the obtained crude intermediate compound of formula IV can be used as such in the subsequent reaction step. However, it may be purified according to usual techniques, such as crystallization.
  • the next reaction step, the introduction of the "good leaving group" -X is conducted by known per se techniques which include, when X is a chlorine, bromine or iodine atom, reacting the hydroxy intermediate of formula IV with the suitable hydrohalidic acid, or preferably, with a suitable halogenating agent which is an inorganic acid halogenide, e.g. SOC1 2 , PCl 5 , PC1 3 , POC1 3 and the like, and when X is a sulfonic acid functional group, reacting the intermediate of formula IV with a sulfonic acid activated derivative, preferably a sulfonic acid halogenide.
  • a suitable halogenating agent which is an inorganic acid halogenide, e.g. SOC1 2 , PCl 5 , PC1 3 , POC1 3 and the like
  • X is a sulfonic acid functional group
  • the reaction is conducted in the presence of an aprotic inert organic solvent such as a halogenated aliphatic hydrocarbon, (e.g. methylene chloride) and chloroform; tetrahydrofuran; an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
  • an aprotic inert organic solvent such as a halogenated aliphatic hydrocarbon, (e.g. methylene chloride) and chloroform; tetrahydrofuran; an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
  • a hydrohalidic acid acceptor preferably a base but more preferably an organic tertiari amine such as a trialkylamine, pyridine, collidine, picoline and the like.
  • R 1 is NR4R5and at least one of R and R is a hydroxy(C 1 -C 4 )alkyl group
  • R may be transformed into the corresponding halogen (C 1 -C 4 ) alkyl by means of known per se halogenation techniques.
  • These halo(C 1 -C 4 )alkyl derivatives of formula I, and preferably the chloro (C 1 -C 4 ) alkyl ones can in turn be reacted with an alkali metal alkoxyde to give the corresponding derivatives of formula I wherein R 4 and/or R represent a (C l -C 4 )alkoxy(C l -C 4 )alkyl group.
  • the triazolo-phthalazine derivatives of formula I wherein R 1 represents the group OR 6 can be prepared by reacting the alcohol intermediate of formula IV with an alkali metal hydride to give the corresponding alkali metal alkoxyde which is then reacted with a compound of formula Y-R 6 wherein R 6 is as above and Y represents chloro, bromo or iodo, to give the desired product of formula I.
  • nitrile derivatives of formula II can be prepared according to the usual procedures, either by reacting the corresponding haloalkyl or sulfonic ester-triazolo-phthalazine with an alkali metal or copper cyanide or by reacting a 1-phthalazino-hydrazine bearing a group of formula (CH 2 ) n-1 -CN in position 4, with the selected benzoylchloride of formula RCOC1, (wherein R is as defined above).
  • the pharmacological properties of the compounds of the present invention were first investigated by submitting some representative members of this class to the benzodiazepine-receptor binding-test in vitro.
  • this test which was carried out by following essentially the method described by H. Möhler and T. Okada in Life Sciences, Vol. 20, 2101-2110 (1977), the affinity of the test compounds for the 3 H-diazepam receptor was quantitatively estimated by measuring the inhibition of specific 3 H-diazepam binding to rat brain membranes by the test compounds.
  • a constant pulsating shocking current is connected between the grid floor and the tap.
  • Each rat is allowed 20 seconds of non-shocked drinking, then cycles of 5 seconds shock-off and*5 seconds shock-on began.
  • each lick on the tap is accompanied by shock.
  • the number of shocks received by each animal is recorded and minimal effective doses are determined.
  • the minimal effective dose is the minimal dose which significantly increases the number of shocks in the treated animals in comparison with controls.
  • the MED of the compound of Example 1 in this test is 5 mg/kg, i.p..
  • Suitable pharmaceutical compositions contain the novel compounds in admixture or conjunction with organic or inorganic, solid or liquic pharmaceutical excipients and may be employed for enteral or parenteral administration.
  • Suitable excipients are substances that do not react with the new compounds, such a: for instance, water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohol, polyalkyleneglycols or other known medicinal excipients.
  • the new compounds may be administered by various routes: while the preferred route of administration is the oral one, intramuscular or intraveneous administration can also be employed.
  • the substances are compounded in forms such as tablets, dispersible powders, capsules, granules, syrups, elixirs and solutions.
  • the active ingredients are embodied into injectable dosage forms.
  • compositions are formulated as known in the art.
  • the dosage regimen for the compounds of the present invention to be used in an anti-anxiety treatment will depend upon a variety of factors including the particular compound used, the route of administration, and the type of treatment applied for. Good results can be obtained, however, by administering the compounds of the present invention at a daily dosage range comprised between about 0.1 and about 2.0 g preferably administered in divided doses. It is however clear that a daily dosage beyond the above indicated range may also be employed depending on the individual conditions of the subject to be treated. Accordingly, the present invention provides a therapeutic composition comprising from about 25 to about 250 mg of one of the compounds of the invention as the active ingredient together with a pharmaceutically acceptable carrier.
  • the active compounds of formula I can be formulated as in the following:
  • the following examples describe the preparation of some representative compounds of the invention. Since the exemplified methods are generally applicable simply by selecting the proper substrates according to the suggestions of the present disclosure, the following examples cannot be construed as limiting the scope of the present invention.
  • N.M.R. and I.R. spectra are in agreement with the assigned structure.
  • the starting 3,4-dihydro-4-oxo-1-phthalazin-acetonitrile is prepared from phthalyl anhydride according to the following method: finely powdered phthalyl anhydride (400 ml), cyanoacetic acid (260 g), anhydrous pyridine (360 ml) are heated at 60°-70°C with stirring for 6 h. The reaction mass is left aside overnight, and then taken up with diluted aqueous hydrochloric acid (1 1) cold stirred for 30 min and filtered. The recovered solid is washed with water and crystallized from acetic acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Anesthesiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP84107562A 1983-07-12 1984-06-29 3,6-Disubstituierte Triazolo[3,4-a]phthalazinderivate Expired EP0134946B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT84107562T ATE28874T1 (de) 1983-07-12 1984-06-29 3,6-disubstituierte triazolo(3,4a>phthalazinderivate.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT22014/83A IT1194310B (it) 1983-07-12 1983-07-12 Derivati triazolo (3,4-a) ftalazinici 3,6-disostituiti
IT2201483 1983-07-12

Publications (2)

Publication Number Publication Date
EP0134946A1 true EP0134946A1 (de) 1985-03-27
EP0134946B1 EP0134946B1 (de) 1987-08-12

Family

ID=11190206

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84107562A Expired EP0134946B1 (de) 1983-07-12 1984-06-29 3,6-Disubstituierte Triazolo[3,4-a]phthalazinderivate

Country Status (9)

Country Link
US (1) US4783461A (de)
EP (1) EP0134946B1 (de)
JP (1) JPS6056982A (de)
AT (1) ATE28874T1 (de)
AU (1) AU560726B2 (de)
CA (1) CA1234114A (de)
DE (1) DE3465309D1 (de)
DK (1) DK164704C (de)
IT (1) IT1194310B (de)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004560A1 (en) * 1996-07-25 1998-02-05 Merck Sharp & Dohme Limited SUBSTITUTED TRIAZOLO PYRIDAZINE DERIVATIVES AS INVERSE AGONISTS OF THE GABAAα5 RECEPTOR SUBTYPE
WO1999006407A1 (en) * 1997-07-29 1999-02-11 Merck Sharp & Dohme Limited THERAPEUTICALLY ACTIVE 1,2,4-TRIAZOLO(4.,3-b) PYRIDAZINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS
WO1999036423A1 (en) * 1998-01-14 1999-07-22 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for gaba receptors
US6046196A (en) * 1997-12-18 2000-04-04 Merck Sharp & Dohme Ltd. Antispastic use of triazolo-pyridazine derivatives
US6063783A (en) * 1997-12-18 2000-05-16 Merck Sharp & Dohme Ltd. Analgesic use of triazolo-pyridazine derivatives
US6107296A (en) * 1997-12-18 2000-08-22 Merck Sharp & Dohme, Ltd. Neuroprotective use of triazolo-pyridazine derivatives
US6110915A (en) * 1997-12-18 2000-08-29 Merck & Co., Inc. Antiemetic use of triazolo-pyridazine derivatives
US6174886B1 (en) 1997-11-13 2001-01-16 Merck Sharp & Dohme Ltd. Antipsychotic use of triazolo-pyridazine derivatives
US6200975B1 (en) 1997-05-08 2001-03-13 Merck Sharp & Dohme Limited Substituted 1,2,4-triazolo[3,4-a]phthalazine derivatives as GABA alpha 5 ligands
US6255305B1 (en) 1996-07-25 2001-07-03 Merck Sharp & Dohme Limited Substituted triazolo-pyridazine derivatives as ligands for GABA receptors
US6291460B1 (en) 1998-01-22 2001-09-18 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for GABA receptors
US6303605B1 (en) 1998-01-21 2001-10-16 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6319924B1 (en) 1998-01-21 2001-11-20 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6355798B1 (en) 1998-01-21 2002-03-12 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6399608B1 (en) 1998-01-23 2002-06-04 Merck Sharp & Dohme Ltd. Combination of a GABA-A α 2/3 agonist and a selective serotonin reuptake inhibitor
US6448249B1 (en) 1998-02-25 2002-09-10 Merck Sharp & Dohme Ltd. Substituted 1,2,4-triazolo[3,4-A]phthalazine derivatives as GABAα5 ligands
US6534505B2 (en) 1998-11-12 2003-03-18 Merck & Co., Inc. Therapeutic polymorphs of a GABA-A alpha-5 inverse agonist and pamoate formulations of the same
US6579875B1 (en) 1998-01-21 2003-06-17 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for GABA receptors
US6613766B1 (en) 1998-11-12 2003-09-02 Merck Sharp & Dohme Ltd. Pentaaza-cyclopental[a]naphthalene derivatives as ligands for GABAa α5 receptors
US6699859B1 (en) 1998-01-21 2004-03-02 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6900209B2 (en) 2000-11-23 2005-05-31 Merck Sharp & Dohme Ltd. Nitrogen substituted 1,2,4-triazolo[3,4-a]phthalazine derivatives for enhancing cognition
US8269037B2 (en) 2009-01-29 2012-09-18 Basf Se Absorption medium for removing acid gases which comprises amino acid and acid promoter

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1303272B1 (it) * 1998-10-29 2000-11-06 Zambon Spa Derivati triciclici inibitori della fosfodiesterasi 4
AU1481701A (en) * 1999-11-12 2001-06-06 Neurogen Corporation Bicyclic and tricyclic heteroaromatic compounds
BRPI0606379A2 (pt) * 2005-01-05 2009-06-23 Nycomed Gmbh triazolftalazinas
JP5130053B2 (ja) * 2005-01-05 2013-01-30 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング トリアゾロフタラジン

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0029130A1 (de) * 1979-10-29 1981-05-27 The Dow Chemical Company 3,6,7,8-Substituierte s-Triazolo(4,3-b)pyridazine, ihre Herstellund und sie enthaltende Zusammensetzungen
EP0085840A1 (de) * 1982-01-18 1983-08-17 Gruppo Lepetit S.P.A. 6-Substituierte s-Triazolo(3,4-a)phthalazin-Derivate

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2484029A (en) * 1945-12-21 1949-10-11 Ciba Pharm Prod Inc Hydrazine derivatives of pyridazine compounds
GB629177A (en) * 1945-12-21 1949-09-14 Ciba Ltd Manufacture of new hydrazine compounds and derivatives thereof
US3711481A (en) * 1970-04-24 1973-01-16 G Hardtmann 6-aryl-imidazo(2,1-a)phthalazines
US3694442A (en) * 1970-07-28 1972-09-26 William J Houlihan SUBSTITUTED TETRAHYDRO-1H-PYRAZOLO{8 1,2-b{9 PHTHALAZINES
US3704300A (en) * 1971-04-09 1972-11-28 Sandoz Ag Imidazo(2,1-a)phthalazines
JPS603080B2 (ja) * 1976-08-10 1985-01-25 三菱化学株式会社 Ｓ―トリアゾロ〔３，４ ―α〕〔５，６，７，８〕テトラヒドロ フタラジン類
US4391807A (en) * 1982-07-12 1983-07-05 The Dow Chemical Company 6-Substituted tetrahydroimidazo[2,1-a]phthalazines and use as bronchodilators
US4485106A (en) * 1982-07-12 1984-11-27 The Dow Chemical Company Substituted tetrahydrotetrazolo[5,1-a]phthalazines
US4487930A (en) * 1982-09-07 1984-12-11 The Dow Chemical Company 6-[(Cyclic amino)alkylamino]-tetrahydrotriazolo[3,4-a]phthalazines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0029130A1 (de) * 1979-10-29 1981-05-27 The Dow Chemical Company 3,6,7,8-Substituierte s-Triazolo(4,3-b)pyridazine, ihre Herstellund und sie enthaltende Zusammensetzungen
EP0085840A1 (de) * 1982-01-18 1983-08-17 Gruppo Lepetit S.P.A. 6-Substituierte s-Triazolo(3,4-a)phthalazin-Derivate

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465462B1 (en) 1996-07-25 2002-10-15 Merck Sharp & Dohme Ltd. Substituted triazolo pyridazine derivatives as inverse agonists of the GABAAα5 receptor subtype
EA002436B1 (ru) * 1996-07-25 2002-04-25 Мерк Шарп Энд Домэ Лимитед Замещенные производные триазоло-пиридазина в качестве лигандов рецепторов гамк
US6255305B1 (en) 1996-07-25 2001-07-03 Merck Sharp & Dohme Limited Substituted triazolo-pyridazine derivatives as ligands for GABA receptors
WO1998004560A1 (en) * 1996-07-25 1998-02-05 Merck Sharp & Dohme Limited SUBSTITUTED TRIAZOLO PYRIDAZINE DERIVATIVES AS INVERSE AGONISTS OF THE GABAAα5 RECEPTOR SUBTYPE
US6200975B1 (en) 1997-05-08 2001-03-13 Merck Sharp & Dohme Limited Substituted 1,2,4-triazolo[3,4-a]phthalazine derivatives as GABA alpha 5 ligands
US6310203B1 (en) 1997-05-08 2001-10-30 Merck Sharpe & Dohme Limited Precursor compounds to substituted 1,2,4-triazolo[3,4,-a]phathalazine GABA alpha 5 ligands
WO1999006407A1 (en) * 1997-07-29 1999-02-11 Merck Sharp & Dohme Limited THERAPEUTICALLY ACTIVE 1,2,4-TRIAZOLO(4.,3-b) PYRIDAZINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS
US6313125B1 (en) 1997-07-29 2001-11-06 Merck Sharp & Dohme Ltd. Therapeutically active 1,2,4-triazolo[4.,3-B] pyridazine derivatives as ligands for GABA receptors
US6174886B1 (en) 1997-11-13 2001-01-16 Merck Sharp & Dohme Ltd. Antipsychotic use of triazolo-pyridazine derivatives
US6046196A (en) * 1997-12-18 2000-04-04 Merck Sharp & Dohme Ltd. Antispastic use of triazolo-pyridazine derivatives
US6110915A (en) * 1997-12-18 2000-08-29 Merck & Co., Inc. Antiemetic use of triazolo-pyridazine derivatives
US6107296A (en) * 1997-12-18 2000-08-22 Merck Sharp & Dohme, Ltd. Neuroprotective use of triazolo-pyridazine derivatives
US6063783A (en) * 1997-12-18 2000-05-16 Merck Sharp & Dohme Ltd. Analgesic use of triazolo-pyridazine derivatives
US6303597B1 (en) 1998-01-14 2001-10-16 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for GABA receptors
WO1999036423A1 (en) * 1998-01-14 1999-07-22 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for gaba receptors
US6579875B1 (en) 1998-01-21 2003-06-17 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for GABA receptors
US6355798B1 (en) 1998-01-21 2002-03-12 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6319924B1 (en) 1998-01-21 2001-11-20 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6303605B1 (en) 1998-01-21 2001-10-16 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6699859B1 (en) 1998-01-21 2004-03-02 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6828322B2 (en) 1998-01-21 2004-12-07 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for GABA receptors
US6291460B1 (en) 1998-01-22 2001-09-18 Merck Sharp & Dohme Limited Triazolo-pyridazine derivatives as ligands for GABA receptors
US6399608B1 (en) 1998-01-23 2002-06-04 Merck Sharp & Dohme Ltd. Combination of a GABA-A α 2/3 agonist and a selective serotonin reuptake inhibitor
US6448249B1 (en) 1998-02-25 2002-09-10 Merck Sharp & Dohme Ltd. Substituted 1,2,4-triazolo[3,4-A]phthalazine derivatives as GABAα5 ligands
US6534505B2 (en) 1998-11-12 2003-03-18 Merck & Co., Inc. Therapeutic polymorphs of a GABA-A alpha-5 inverse agonist and pamoate formulations of the same
US6613766B1 (en) 1998-11-12 2003-09-02 Merck Sharp & Dohme Ltd. Pentaaza-cyclopental[a]naphthalene derivatives as ligands for GABAa α5 receptors
US6900209B2 (en) 2000-11-23 2005-05-31 Merck Sharp & Dohme Ltd. Nitrogen substituted 1,2,4-triazolo[3,4-a]phthalazine derivatives for enhancing cognition
US8269037B2 (en) 2009-01-29 2012-09-18 Basf Se Absorption medium for removing acid gases which comprises amino acid and acid promoter

Also Published As

Publication number Publication date
DK331884A (da) 1985-01-13
ATE28874T1 (de) 1987-08-15
US4783461A (en) 1988-11-08
IT1194310B (it) 1988-09-14
EP0134946B1 (de) 1987-08-12
JPH051267B2 (de) 1993-01-07
JPS6056982A (ja) 1985-04-02
DK331884D0 (da) 1984-07-06
DE3465309D1 (de) 1987-09-17
DK164704B (da) 1992-08-03
DK164704C (da) 1992-12-21
AU560726B2 (en) 1987-04-16
IT8322014A0 (it) 1983-07-12
CA1234114A (en) 1988-03-15
AU3022484A (en) 1985-01-17

Similar Documents

Publication Publication Date Title
EP0134946B1 (de) 3,6-Disubstituierte Triazolo[3,4-a]phthalazinderivate
EP0989129B1 (de) Pyrazolopyridylpyrazinon-derivate und ein verfahren zu ihrer herstellung
CA1214168A (en) 6-substituted-s-triazole¬3,4-a|phthalazine derivatives
EP0591528B1 (de) PYRAZOLO[1,5-a]PYRIMIDINDERIVATE UND SIE ENTHALTENDE ANTIINFLAMMATORISCHE MITTEL
EP1012151B1 (de) Heterocyclyl-substituierte annellierte pyridine und pyrimidine als antagonisten des corticotropin freisetzenden hormons (crh), verwendbar für die behandlung von cns und stress
KR910004450B1 (ko) 3-아크릴아미노메틸이미다조[1,2-a]피리딘 유도체, 그의 제법 및 그를 포함하는 의약조성물
KR900006753B1 (ko) 6-아미노-7-히드록시-4,5,6,7-테트라히드로이미다조[4,5,1-j-k][1]-벤즈아제핀-2(1H)-온 유도체 및 그것의 염의 제조방법
US20030158203A1 (en) Triazolo-pyridazine derivatives as ligands for GABA receptors
EP0362695A1 (de) Pyrrolocarbazol-Derivate, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE69200895T2 (de) 3-Aminopyridazinderivaten mit einer Wirkung auf das zentrale Nervensystem.
HU215394B (hu) 3-Fenil-izokinolin-1(2H)-on-származékok, eljárás előállításukra és a vegyületeket tartalmazó gyógyszerkészítmények
EP0370236A1 (de) Indolocarbazol-Derivate, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
CN112939982A (zh) 一种炔类杂环btk抑制剂及其制备方法和用途
WO2000047582A1 (en) Triazolo-pyridazine derivatives as ligands for gaba receptors
US5276028A (en) Imidazoquinoxaline compounds
US5100895A (en) Heterocyclic compounds and their preparation and use
GB2096143A (en) Imidazo(1,2-a)quinoline derivatives
JPS63166876A (ja) ピリドンカルボン酸誘導体
EP0535104A1 (de) Heterocyclische verbindungen, herstellung und verwendung.
EP0134461B1 (de) Pyridazino[4,3-c]isochinolinderivate
CN115960109B (zh) 稠环类shp2磷酸酶抑制剂的制备及其应用
US5972930A (en) Pyridinylamino tricyclic compounds as substance P antagonists
JPS6124594A (ja) 複素環化合物のアリール誘導体
PL174418B1 (pl) Nowe związki, pochodne pirydo [1,2,3-de] chinoksaliny i sposób wytwarzania nowych związków, pochodnych pirydo [1,2,3-de] chinoksaliny
KR800000854B1 (ko) 나프티리딘 유도체의 제법

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17P Request for examination filed

Effective date: 19850803

17Q First examination report despatched

Effective date: 19860609

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

REF Corresponds to:

Ref document number: 28874

Country of ref document: AT

Date of ref document: 19870815

Kind code of ref document: T

ET Fr: translation filed
REF Corresponds to:

Ref document number: 3465309

Country of ref document: DE

Date of ref document: 19870917

ITF It: translation for a ep patent filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: GRUPPO LEPETIT S.P.A.

ITTA It: last paid annual fee
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19920323

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19920402

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19920403

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19920630

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19920710

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19920803

Year of fee payment: 9

EPTA Lu: last paid annual fee
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19930316

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19930329

Year of fee payment: 10

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19930629

Ref country code: AT

Effective date: 19930629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19930630

Ref country code: LI

Effective date: 19930630

Ref country code: CH

Effective date: 19930630

Ref country code: BE

Effective date: 19930630

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19930630

Year of fee payment: 10

BERE Be: lapsed

Owner name: GRUPPO LEPETIT S.P.A.

Effective date: 19930630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19940101

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19940629

EUG Se: european patent has lapsed

Ref document number: 84107562.5

Effective date: 19940110

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19940629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19950228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19950301

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST